The proposed grant will study the acute and long-term effects of methadone on behavior, brain serotonin (5-HT) function, pituitary-adrenal responsiveness to stress and reproduction using experimental animals. The major objective of this study will be to evaluate these effects in view of the human treatment mode in the narcotic addict. Acute experiments will study the importance of serotonin systems on the ability of methadone to act as a discriminative-cue in a state-dependent model of behavior. 5-HT systems will be manipulated by the use of amine synthesis inhibitors, and by the electrostimulation and lesioning of raphe systems in the rat. In the chronic phase of this study, serotonin and pituitary-adrenal function will be evaluated in rats exposed to acute psychological procedures which are stressful. The length of estrous cycles, frequency of ovulation, ability to conceive, deliver and nurse pups, and time of vaginal opening in methadone-treated animals will be compared with the same functions in vehicle-treated rats. The site at which any deficit occurs will be investigated by studying blood levels of pituitary hormones, the responsiveness of the brain to intraventricular catecholamine injections or electrical stimulation, the responsiveness of the adenohypophysis to LH-RH, and the responsiveness of the ovary to LH.